The present proposal is designed to create a model of persistent pulmonary hypertension of the newborn in the guinea pig in two ways: (1) Indomethacin, a prostaglandin synthetase inhibitor will be given intravenously to the pregnant mother over the last two weeks of gestation to constrict the ductus arteriosus of the fetus; (2) Pregnant guinea pigs will be subjected to chronic hypobaric hypoxia to cause fetal pulmonary vasoconstriction. The physiology of persistent pulmonary hypertension of the newborn will be confirmed by hemodynamic studies in which pulmonary and systemic artery pressures will be monitored and right to left shunting assessed. At postmortem, after injecting the pulmonary arteries with barium gelatin and inflating the lung with formalin, quantitative morphometric analysis of the pulmonary vascular bed will be carried out. Their evidence of structural remodeling will be determined and in particular to what degree precocious muscularization of the fetal arteries has occurred. We will reverse or at least diminish the persistent pulmonary hypertension of the newborn guinea pigs acutely, by using a wide variety of vasodilators with different mechanisms of action, including oxygen, tolazoline, hexaprenaline, nitroprusside, PGE1, PGI2, captopril, verapamil. From these, the most potent will be selected for chronic administration. We will then determine whether lowering the level of pulmonary hypertension will reverse the structural changes of the pulmonary vascular bed and thus alter the course of the disease. We will, through these studies gain insight into the specific sensitivity of the newborn pulmonary circulation. Many of the therapeutic agents selected are experimental, but have deleterious systemic effects. Should we prove their effectiveness in an animal model their application to sick newborns with persistent pulmonary hypertension will follow.